Strain‐specific red blood cell storage, metabolism, and eicosanoid generation in a mouse model

Zimring, James C.; Smith, Nicole H.; Stowell, Sean R.; Johnsen, Jill M.; Bell, Lauren N.; Francis, Richard O.; Hod, Eldad A.; Hendrickson, Jeanne E.; Roback, John D.; Spitalnik, Steven L.

doi:10.1111/trf.12264

Cited by 79 publications

(110 citation statements)

References 29 publications

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“…We previously utilized this model to identify metabolic patterns that correlated with good storage (RBCs from C57BL/6 mice) or poor storage (RBCs from FVB mice) [70]. Since the present data utilized the same analysis platform, we can compare the murine results with metabolic changes of human RBCs stored in AS-1.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics of ADSOL (AS-1) Red Blood Cell Storage

Roback

Josephson

Waller

et al. 2014

Transfusion Medicine Reviews

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109

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Background Population based investigations suggest that red blood cells (RBCs) are therapeutically effective when collected, processed and stored for up to 42 days under validated conditions prior to transfusion. However, some retrospective clinical studies have shown worse patient outcomes when transfused RBCs have been stored for the longest times. Furthermore, studies of RBC persistence in the circulation after transfusion have suggested that considerable donor-to-donor variability exists, and may affect transfusion efficacy. To understand the limitations of current blood storage technologies and to develop approaches to improve RBC storage and transfusion efficacy, we investigated the global metabolic alterations that occur when RBCs are stored in AS-1 (AS1-RBC). Methods Leukoreduced AS1-RBC units prepared from 9 volunteer research donors (12 total donated units) were serially sampled for metabolomics analysis over 42 days of refrigerated storage. Samples were tested by GC/MS and LC/MS/MS, and specific biochemical compounds were identified by comparison to a library of purified standards. Results Over three experiments, 185–264 defined metabolites were quantified in stored RBC samples. Kinetic changes in these biochemicals confirmed known alterations in glycolysis and other pathways previously identified in RBCs stored in SAGM (SAGM-RBC). Furthermore, we identified additional alterations not previously seen in SAGM-RBCs (e.g., stable pentose phosphate pathway flux, progressive decreases in oxidized glutathione), and we delineated changes occurring in other metabolic pathways not previously studied (e.g., S-adenosyl methionine cycle). These data are presented in the context of a detailed comparison with previous studies of SAGM-RBCs from human donors and murine AS1-RBCs. Conclusion Global metabolic profiling of AS1-RBCs revealed a number of biochemical alterations in stored blood that may affect RBC viability during storage as well as therapeutic effectiveness of stored RBCs in transfusion recipients. Significance These results provide future opportunities to more clearly pinpoint the metabolic defects during RBC storage, to identify biomarkers for donor screening and prerelease RBC testing, and to develop improved RBC storage solutions and methodologies.

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Section: Discussionmentioning

confidence: 99%

Metabolomics of ADSOL (AS-1) Red Blood Cell Storage

Roback

Josephson

Waller

et al. 2014

Transfusion Medicine Reviews

Self Cite

109

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“…In this setting, the same lipid oxidation pathways are associated with poor storage. 29 In addition, dicarboxylic acids remain associated with poor storage in leukoreduced RBCs (data not shown). Thus, while some of the associated change may be due to contaminating leukocytes and/or platelets, the major findings of lipid peroxidation persist even with leukoreduction.…”

Section: Discussionmentioning

confidence: 99%

Metabolic pathways that correlate with post-transfusion circulation of stored murine red blood cells

Wolski

Dumont³

et al. 2016

Haematologica

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T ransfusion of red blood cells is a very common inpatient procedure, with more than 1 in 70 people in the USA receiving a red blood cell transfusion annually. However, stored red blood cells are a non-uniform product, based upon donor-to-donor variation in red blood cell storage biology. While thousands of biological parameters change in red blood cells over storage, it has remained unclear which changes correlate with function of the red blood cells, as opposed to being co-incidental changes. In the current report, a murine model of red blood cell storage/transfusion is applied across 13 genetically distinct mouse strains and combined with high resolution metabolomics to identify metabolic changes that correlated with red blood cell circulation post storage. Oxidation in general, and peroxidation of lipids in particular, emerged as changes that correlated with extreme statistical significance, including generation of dicarboxylic acids and monohydroxy fatty acids. In addition, differences in anti-oxidant pathways known to regulate oxidative stress on lipid membranes were identified. Finally, metabolites were identified that differed at the time the blood was harvested, and predict how the red blood cells perform after storage, allowing the potential to screen donors at time of collection. Together, these findings map out a new landscape in understanding metabolic changes during red blood cell storage as they relate to red blood cell circulation. ABSTRACT

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“…Although the clinical consequences of such differences have not been established in humans, studies in mice have demonstrated strain-specific susceptibility to RBC injury from cold storage that correlates with posttransfusion RBC recovery and function. 8,9 …”

Section: Introductionmentioning

confidence: 99%

Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study

et al. 2017

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Genetic polymorphisms in blood donors may contribute to donor-specific differences in the survival of red blood cells (RBCs) during cold storage and after transfusion. Genetic variability is anticipated to be high in donors with racial admixture from malaria endemic regions such as Africa and Asia. The purpose of this study was to test the hypothesis that donor genetic background, reflected by sex and self-reported ethnicity, significantly modulates RBC phenotypes in storage. High throughput hemolysis assays were developed and used to evaluate stored RBC samples from 11 115 African American, Asian, white, and Hispanic blood donors from 4 geographically diverse regions in the United States. Leukocyte-reduced RBC concentrate-derived samples were stored for 39 to 42 days (1–6°C) and then evaluated for storage, osmotic, and oxidative hemolysis. Male sex was strongly associated with increased susceptibility to all 3 hemolysis measures (P < .0001). African American background was associated with resistance to osmotic hemolysis compared with other racial groups (adjusted P < .0001). Donor race/ethnicity was also associated with extreme (>1%) levels of storage hemolysis exceeding US Food and Drug Administration regulations for transfusion (hemolysis >1% was observed in 3.51% of Asian and 2.47% of African American donors vs 1.67% of white donors). These findings highlight the impact of donor genetic traits on measures of RBC hemolysis during routine cold storage, and they support current plans for genome-wide association studies, which may help identify hereditable variants with substantive effects on RBC storage stability and possibly posttransfusion outcomes.

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Strain‐specific red blood cell storage, metabolism, and eicosanoid generation in a mouse model

Cited by 79 publications

References 29 publications

Metabolomics of ADSOL (AS-1) Red Blood Cell Storage

Metabolomics of ADSOL (AS-1) Red Blood Cell Storage

Metabolic pathways that correlate with post-transfusion circulation of stored murine red blood cells

Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study

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